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Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy


Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.

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Figure 1: Individuals with mutations in PLK4 or TUBGCP6 exhibit extreme microcephaly and short stature.
Figure 2: Consequences of PLK4 mutations on the transcript and protein.
Figure 3: PLK4 mutations impair PLK4 activity in centriole biogenesis, resulting in reduced centriole number in patient-derived cells.
Figure 4: Depletion of plk4 causes dwarfism in zebrafish.
Figure 5: Impaired mitosis leads to growth retardation in plk4-morphant zebrafish.
Figure 6: plk4-morphant zebrafish display retinal defects due to reduced cilia number.
Figure 7: The growth failure and ciliopathy phenotypes are separable in a dose-dependent manner.


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We thank the families and clinicians for their involvement and participation; P. Mills, T. Hurd, M. Bettencourt-Dias and M. Reijns for commenting on the manuscript; N. Hastie, D. Fitzpatrick and J. Livingston for helpful discussions; C. Janke (Institut Curie) for his kind gift of the GT335 antibody; E. Freyer for assistance with FACS analysis; P. Gautier for bioinformatics; P. Carroll and A. Vickers for technical assistance; the IGMM core sequencing service; the IGMM imaging facility for assistance with microscopy; E. Patton and the IGMM fish facility for advice and zebrafish technical assistance; E. Liston and the DNA Resource Centre at SickKids for sample processing; A. Pearce and E. Maher (Cytogenetics Laboratory, South East Scotland Genetics Service) for technical advice; G. Hahn (University Hospital Carl Gustav Carus) for her second opinion on the MRI data; and N. Dalibor and E. Kirst (CCG) for their expert technical assistance. This work was supported by funding from the MRC, the Lister Institute for Preventative Medicine and the European Research Council (ERC, 281847) (A.P.J.), Medical Research Scotland (L.S.B.), the National Institute for Health Research Moorfields Eye Hospital Biomedical Research Centre (A.T.M.), Köln Fortune (M.S.H.) and CMMC (P.N. and A.A.N.).

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P.N., H.T., J.A., M.S.H., A.B., K.M., M.E. Hurles, J.E.M. and L.S.B. performed exome sequencing and analysis. L.S.B., C.-A.M., J.E.M., M.R.T., I.A., M.S.H. and G.N. performed sequencing, genotyping, linkage analysis and other molecular genetics experiments. C.-A.M., A.L., C.K., M.E. Harley, I.A., M.S.H., R.M., A.A.N. and I.H. designed and performed the cell biology experiments. A. Klingseisen designed and performed the zebrafish experiments with help from A.L., C.-A.M., J.D. and P.H. W.H. performed structural analysis. D.H., F.K., Z.A., S.T., V.C.-D., H.D., L.D., A. Kariminejad, R.M.-L., A.T.M., A.S., C.S., R.W. and S.M.B. ascertained subjects, obtained samples and/or assisted with phenotypic analysis and clinical studies. C.-A.M. and A.P.J. wrote the manuscript with help from P.N., A. Klingseisen and L.S.B. The study was planned and supervised by P.N. and A.P.J.

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Correspondence to Peter Nürnberg or Andrew P Jackson.

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Competing interests

P.N. is a founder, CEO and shareholder of ATLAS Biolabs. ATLAS Biolabs is a service provider for genomic analyses.

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Supplementary Figures 1–17, Supplementary Tables 1–3 and Supplementary Note. (PDF 3515 kb)

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Martin, CA., Ahmad, I., Klingseisen, A. et al. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet 46, 1283–1292 (2014).

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